| Title: |
Dynamin impacts homology-directed repair and breast cancer response to chemotherapy |
| Authors: |
Chernikova Sophia B; Nguyen Rochelle B; Truong Jessica T; Mello Stephano S; Stafford Jason H; Hay Michael P; Olson Andrew; Solow-Cordero David E; Wood Douglas J; Henry Solomon; von Eyben Rie; Deng Lei; Gephart Melanie Hayden; Aroumougame Asaithamby; Wiese Claudia; Game John C; Győrffy, Balázs; Brown J Martin |
| Contributors: |
SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika; Semmelweis Egyetem |
| Publication Year: |
2018 |
| Collection: |
Semmelweis Egyetem: Repozitórium |
| Description: |
After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
0021-9738 |
| Relation: |
urn:issn:0021-9738; http://repo.lib.semmelweis.hu//handle/123456789/6827; 000452071300018 |
| DOI: |
10.1172/JCI87191 |
| Availability: |
http://repo.lib.semmelweis.hu//handle/123456789/6827; https://doi.org/10.1172/JCI87191 |
| Rights: |
NULL |
| Accession Number: |
edsbas.51479CD2 |
| Database: |
BASE |